Synthesis and Structure Activity Relationship of Organometallic Steroidal Androgen Derivatives

Abstract

We present here the synthesis and the structure activity relationship of a series of organometallic complexes of the steroidal androgens testosterone and dihydrotestosterone (DHT) substituted at the C-17 position of the steroid skeleton with an ethynyl substituent grafted with various sandwich or semisandwich organometallic units [ferrocenyl, (η 5 -C 5 H 4 )-Re(CO) 3 , (η 5 -C 5 H 4 )-Mn(CO) 3 , (η 6 -C 6 H 5 )-Cr(CO) 3 ] and of 3 -androstanediol substituted at C-16 and C-17 respectively by a ferrocenyl vinyl and a ferrocenyl ethynyl unit. In contrast to the estradiol series, there are currently very few examples of organometallic steroidal androgens in the literature. The ethynyltestosterone derivatives were obtained via a Stille coupling reaction between the appropriate iodo-organometallics and 17 -ethynyltestosterone stannyl derivatives. The ethynyl-DHT derivatives were synthesized by addition of the corresponding acetylide to the C-17 carbonyl of the steroid. The crystal structures of two ferrocenyl and one rhenium complexes were determined by X-ray diffraction and had confirmed that the organometallic moiety points toward the R face of the steroid skeleton. All the complexes retain a modest affinity for the androgen receptor. The ferrocenyl derivatives of ethynyl testosterone, 8 and 12, show a strong antiproliferative effect on the hormoneindependent prostate cancer cells PC-3 with IC 50 values of respectively 4.7 and 8.3 µM. These values are very similar, for 12, or slightly better, for 8, than those found recently for the most active ferrocenyl derivative of the nonsteroidal antiandrogen nilutamide (IC 50 value of 5.4 µM). The ferrocenyl complexes described here are the first examples of organometallic steroidal androgens possessing a strong antiproliferative activity on prostate cancer cells.

Synthesis, Cytotoxicity, and COMPARE Analysis of Ferrocene and [3]Ferrocenophane Tetrasubstituted Olefin Derivatives against Human Cancer Cells

“…Another class demonstrates the enthusiasm researchers have for grafting metallocenes and metal carbonyls to a variety of biomolecules to modify their biological effects. [12] These therapeutic bioconjugates include steroidal [13][14][15] and nonsteroidal [16][17][18][19][20][21][22][23] endocrine modulators, natural products, [24][25][26][27] and others. [28][29][30][31][32][33][34] In these cases, the often covalently grafted organometallic unit is usually inert to ligand substitution, but potentiates the activity of the biomolecule via modification of the pharmacokinetic profile or acts as a structural mimic.…”

Selective cytotoxicity of arene tricarbonylchromium towards tumour cell lines

“…Arene tricarbonylchromium group, for which the oxidation state of chromium is zero, has been attached to biological substances such as β-estradiol molecule to produce complexes that have been mainly studied for their capacity to act as a probe for the detection of biological substances by infrared spectroscopy [30]. One of the chromium complexes was recognized by androgen receptor [31]. It has been found that tricarbonylchromium compounds can release carbon monoxide for application in therapy.…”

Design and Synthesis of a New Androgen Derivative using Some Strategies

“…The second stage was achieved by reaction of the compound 3 with testosterone ( Figure 2) resulting in imino bond formation involved in the compound 5(10,13-Dimethyl-3-{2-[( [1,10]phenanthrolin-5-ylmethyl)-amino]-ethylimino}-2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ol).It is notewor thy thatthere are several proceduresfor the synthesisofiminogroups are previously described intheliterature [13][14][15] ; for example the synthesis of a steroid derivative by the reaction of N 1 -(2,3-dimethoxystrychnidin-10-yliden)-ethane-1,2-diamine with a steroid derivative using boric acid as catalyst 4 . For this reason, in this study this reagent was used as catalyst in the reaction of the compound 3 with testosterone ( Figure 1) to form the compound 5.The 1 H NMR spectrum of 5 shows signals at 0.80 and 1.02 ppm for methyl groups; at 0.92-1.00, 1.06-2.38, 3.68 and 5.90 ppm for steroid nucleus; at 3.04 and 3.50 ppm for methylene groups bound to both imino and amino groups; at 4.10 ppm for methylene group bound to both phenyl and amino groups; at 4.70 ppm for both amino and hydroxyl groups; at 7.00-7.80 for phenanthroline fragment.…”

“…Finally, the presence of compound 5was further confirmed from mass spectrum which showed a molecular ion at m/z 522.30. The third stepwas achieved bythe synthesisof7(Chloro-acetic acid 3-((3-chloro-2-oxocyclobutyl)-{2-[(3-chloro-2-oxo-cyclobutyl)- [1,10] phenanthrolin-5-ylmethyl-amino]ethyl}-amino)-10,13-dimethyl-2, 3,6,7,8,9,10,11,12, 13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl ester)byreactionof 5with chloroacetylchloride in the presenceoftriet-hylamine.This method has been previously reported for other type of compound withbothaminoand iminogroupsinvolved in its structure chemical, which react with chloroacetylchloride to form cyclobutanone groups 16 .However, it isnoteworthy that hydroxylgroupof compound 5 was esterified with acetylchloride. This phenomenon is similar to esterification of other type of compounds 17,18 .…”

“…androsten-17-ol-3-one by the reaction of 17-ethynyl-4-androsten-17-ol-3-one with Bu 3 SnOMe to reflux 1 . Other data indicate the preparation of 3-oxoandrost-4-en-17-yl-2-methyl-1H-imidazole-1-carboxylate by the reaction of 17-hydroxyandrost-4-en-3-one-1,1-carbonylbis(2-methylimidazole) in anhydrous acetonitrile 2 .…”